Effector mechanisms of the autoimmune syndrome in the murine model of autoimmune polyglandular syndrome type 1.
Effector mechanisms of the autoimmune syndrome in the murine model of autoimmune polyglandular syndrome type 1.
复制标题
自身免疫性多边形综合征1型的鼠模型中自身免疫综合征的效应器机制。
DOI：
10.4049/jimmunol.181.6.4072
复制
发表时间：
2008-09-15
影响因子：
4.4
通讯作者：
Anderson, Mark S.
中科院分区：
文献类型：
--
作者：
DeVoss, Jason J.;Shum, Anthony K.;Johannes, Kellsey P. A.;Lu, Wen;Krawisz, Anna K.;Wang, Peter;Yang, Ting;LeClair, Norbert P.;Austin, Cecilia;Strauss, Erich C.;Anderson, Mark S.
自身免疫调节因子（Aire）基因的突变导致称为自身免疫多腺体综合征I型（APS 1）的临床现象，其典型表现为肾上腺功能不全、甲状旁腺功能减退和慢性皮肤粘膜感染的三联征。除了这三种疾病之外，在APS 1患者中还观察到许多其他自身免疫性疾病，包括干燥综合征、白癜风、脱发、葡萄膜炎等。Aire缺陷小鼠，APS 1的动物模型，突出了胸腺在疾病过程中的作用，并证明了Aire缺陷小鼠中枢耐受性的失败。然而，在小鼠和人类中都观察到了针对多个器官的自身抗体，这使得目前尚不清楚B和T细胞在疾病发病机制中的具体作用。利用aire缺陷小鼠作为APS 1的临床前模型，我们研究了特定淋巴细胞群体的相对贡献，目的是鉴定可能用于合理治疗设计的细胞群体。在这里，我们表明，T细胞是必不可少的自我耐受性的崩溃，相反，B细胞在自身免疫中发挥更有限的作用。特别是Th1极化的CD4+ T细胞是自身免疫应答的主要贡献者。有了这些知识，我们继续利用靶向T细胞的疗法来研究它们在体内调节疾病的能力。使用中和抗体消耗CD4+ T细胞改善了疾病过程。因此，特异性靶向CD4+ T细胞亚群的治疗可能有助于控制APS 1患者的自身免疫性疾病。
Mutations in the Autoimmune regulator (Aire) gene result in a clinical phenomenon known as Autoimmune Polyglandular Syndrome Type I (APS1), which classically manifests as a triad of adrenal insufficiency, hypoparathyroidism, and chronic mucocutaneous infections. In addition to this triad, a number of other autoimmune diseases have been observed in APS1 patients including Sjögren's syndrome, vitiligo, alopecia, uveitis, and others. Aire-deficient mice, the animal model for APS1, have highlighted the role of the thymus in the disease process and demonstrated a failure in central tolerance in aire-deficient mice. However, autoantibodies have been observed against multiple organs in both mice and humans, making it unclear what the specific role of B and T cells are in the pathogenesis of disease. Utilizing the aire-deficient mouse as a preclinical model for APS1, we have investigated the relative contribution of specific lymphocyte populations, with the goal of identifying the cell populations which may be targeted for rational therapeutic design. Here we show that T cells are indispensable to the breakdown of self-tolerance, in contrast to B cells which play a more limited role in autoimmunity. Th1 polarized CD4+ T cells, in particular, are major contributors to the autoimmune response. With this knowledge, we go on to utilize therapies targeted at T cells to investigate their ability to modulate disease in vivo. Depletion of CD4+ T cells using a neutralizing antibody ameliorated the disease process. Thus, therapies targeted specifically at the CD4+ T cell subset may help control autoimmune disease in patients with APS1.
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DOI：
10.1084/jem.20061577
发表时间：
2006-11-27
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Fife BT;Guleria I;Gubbels Bupp M;Eagar TN;Tang Q;Bour-Jordan H;Yagita H;Azuma M;Sayegh MH;Bluestone JA
通讯作者：
Bluestone JA
DOI：
10.1084/jem.20050693
发表时间：
2005-09-19
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Jiang W;Anderson MS;Bronson R;Mathis D;Benoist C
通讯作者：
Benoist C
影响因子：
64.8
作者：
MOMBAERTS, P;CLARKE, AR;TONEGAWA, S
通讯作者：
TONEGAWA, S
影响因子：
5.1
作者：
Lankisch, TO;Strassburg, CP;Jacquemin, E
通讯作者：
Jacquemin, E
影响因子：
56.9
作者：
Anderson, MS;Venanzi, ES;Mathis, D
通讯作者：
Mathis, D